Biomedical Engineering Reference
In-Depth Information
well-known side effects of this class of drugs [
172
,
173
]. Several tocainide analogs
were designed and synthesized to obtain novel potent voltage- and use-dependent
skeletal muscle sodium channel blockers, also with the aim of identifying the
structural requirements for ameliorating the therapeutic profile [
174
-
177
].
3.3.3 Cardiovascular Diseases
The ideal Na
+
blocker for the treatment of cardiac diseases should interact selec-
tively with the Na
V
1.5 isoform but, unfortunately, the sodium channel blockers in
clinical use are neither isoform nor even channel selective [
82
,
178
]. For example,
class I antiarrhythmics, such as quinidine, procainamide, and disopyramide (class Ia
agents) as well as lidocaine, mexiletine, tocainide and phenytoin (class Ib agents)
and encainide, flecainide, moricizine, and propafenone (class Ic agents) are poten-
tially pro-arrhythmic and with many other side effects due to their nonselective
action, thus resulting contraindicated in several diseases (i.e., encainide is no longer
used) (formulas of these molecules are reported in Figs.
3
-
6
).
KC12292 (Fig.
7
) is a thiadiazole derivative with antiischemic properties in the
early stages of development [
179
]. This compound inhibits the inward peak I
Na
also
by inducing a reduction of the sustained component (or slowly or noninactivating)
of sodium current [
180
]. These characteristics distinguish KC12291 from conven-
tional VGSC blockers with no cardioprotective properties, making this molecule
particularly promising for the treatment of ischemic conditions [
181
].
Ranolazine, approved in the USA by the FDA in 2006, is a new drug useful for
the treatment of chronic angina pectoris in patients with ischemic heart disease
[
182
,
183
] (Fig.
7
). It reduces the late I
Na
and, consequently, it affects the sodium-
H
3
C
H
N
H
3
C
N
NH
2
O
NH
O
tocainide
H
2
N
CF
3
procainamide
OO
HN
H
N
O
O
NH
2
CF
3
Fig. 5 Sodium channel
blockers
mexiletine
flecainide
